Efficacy of generic sofosbuvir with daclatasvir compared to sofosbuvir/ledipasvir in genotype 4 hepatitis C virus: A prospective comparison with historical control

Abstract Background and Aim Management of genotype 4 hepatitis C virus (HCV) has shifted to interferon‐free regimens with a high sustained virological response (SVR‐12), especially with NS5B/NS5A inhibitor combinations such as sofosbuvir and ledipasvir (Sof‐Led). The guidelines have recommended the combination of sofosbuvir and another NS5A inhibitor, daclatasvir, to manage HCV genotypes 1–3. However, its use was extended to genotype 4 HCV based on extrapolating evidence. Our aim is to assess the efficacy of generic sofosbuvir + branded daclatasvir (Sof‐Dac) compared to the Sof‐Led combination in treating genotype 4 HCV. Methods This study is an open‐label, 2‐period, noninferiority study that compared patients receiving a combination of generic sofosbuvir 400 mg and daclatasvir 60 mg orally daily (Group 2) prospectively to a historical control (Group 1) that included patients who received a combination of sofosbuvir/ledipasvir 400/90 mg orally daily. The primary endpoint is the proportion of patients who achieved SVR‐12. Results The study included 111 patients in the (Sof‐Led) Group 1 and 109 patients (Sof‐Dac) Group 2. For the primary outcome, SVR‐12 was achieved in 106 (95.5%) of the patients in Group 1 versus 108 (99.1%) in Group 2 (p = 0.2). In addition, all patients who achieved SVR‐12 also achieved SVR‐24. Conclusion Generic sofosbuvir combined with branded daclatasvir was safe and effective for treating genotype 4 HCV compared to Sof‐Led. This combination may significantly reduce the cost burden, enabling a larger pool of treated patients. Office of research affairs at KFSHRC RAC# 2171 036.


Chronic hepatitis C virus (HCV) infection affects 58 million people
universally; it is associated with a high mortality rate reaching 290,000 deaths annually. 1 In patients with long-standing, well-established HCV infection, disease progression is associated with considerable morbidity and a high-cost burden. 2 HCV complicated by cirrhosis or hepatocellular carcinoma is one of the most common liver transplantation indications. 3,4 The risk of recurrence of HCV posttransplant is considerably high in all patients; however, the risk is even higher in those patients who were viremic at the time of transplantation, leading to a worse prognosis of the disease and graft loss. 5 There have been multiple studies that aimed to determine the prevalence of HCV in Saudi Arabia. The overall prevalence is estimated to fall between 0.3% and 1.1%. [6][7][8] HCV genotype 4 was identified as the most prevalent genotype in the Saudi population, followed by genotype 1. Genotypes 2a/2b emerged from the Eastern Province and genotype 5 from the Western Province, whereas genotypes 3 and 6 remain extremely rare. [9][10][11][12] The treatment of HCV has rapidly evolved over the past several years. For decades, treatment options were limited to ribavirin/ interferon combination, which was poorly tolerated and required prolonged therapy (up to 48 weeks for genotypes 1 and 4) with a reduced response rate; sustained virological response (SVR) of less than 50%. The approval of new oral, direct-acting antiviral (DAA) agents has revolutionized patients' management of HCV. DAAs are associated with better safety and efficacy profiles, shorter treatment duration, and improved outcomes (SVR > 90%). [13][14][15][16] Patients with HCV genotype 4, the most predominant genotype in Saudi Arabia, are poorly represented in most clinical trials involving DAAs. The American Association for the Study of Liver Disease includes sofosbuvir/ledipasvir (Sof-Led) as one of the first-line therapies for managing HCV genotype 4, but not sofosbuvir and daclatasvir combinations. 17 Despite the revolutionary nature of DAA therapy, one of the main challenges regarding adopting DAAs has been the high cost of these medications. In 2016, generic sofosbuvir became available in Saudi Arabia, significantly reducing HCV treatment's overall cost. Our institution has adopted generic sofosbuvir plus daclatasvir as the first-line regimen to treat HCV genotype 4. Despite the favorable cost savings potential, there were some concerns about the efficacy of the generic sofosbuvir and daclatasvir combination compared to the previous first-line regimen in our institution of sofosbuvir/ledipasvir. This study's main objective was to assess generic sofosbuvir's efficacy and safety plus daclatasvir (Sof-Dac) compared with (Sof-Led).

| Outcomes
The primary study endpoint was the proportion of patients achieving an SVR-12 defined as serum HCV RNA below the lower limit of quantification (LLoQ, 30 IU/ml) 12 weeks after the end of test. The SVR is defined as achieving aviremia and viral load detection 12 weeks after EOT. Failure to achieve SVR could reflect relapse, recurrence, or nonresponse. Relapse is defined as achieving early virological response (EVR) at 1 month (4 weeks after initiation of treatment), but EOT response. Recurrence is defined as failure to achieve SVR-12 after a prior achievement of EVR and EOT response. Nonresponse is defined as failure to achieve both EVR and EOT response. Any adverse event was systematically captured for all patients during clinic visits in the prospective group. For the historical group, we depended on documentation in the electronic patient record.

| Statistical analysis and data collection
The study was designed to include 102 subjects in each group. The sample size was determined based on a noninferiority margin of 9% between the proportions of SVR-12 in the two treatment groups and type I and type II errors rates of 0.05 and 0.2, respectively. Unless noted otherwise, a comparison of continuously-scaled data between the two treatment groups was described with means and standard deviations and evaluated with two-sample t-tests. Inferential

| RESULTS
During the study period, we included 111 patients in Group 1 and 109 patients in Group 2 ( Figure 1). Baseline demographics are presented in Table 1.    Table 2. in the CTP at 12 weeks for these two groups were: two improving, three worsening, and 36 no change in Groups 1 and 2, 2 and 24 in Group 2 (p > 0.99). In Group 1 (Sof-Led), two patients had improved CTP scores moving from score B to score A. Both were treatment naïve and received 12 weeks of treatment, and one was treated with ribavirin. On the other hand, three patients had worsened CTP scores: two from score A to B, and one from score B to C. One of those who went from A to B received 8 weeks of treatment. All of them were treatment naïve. In Group 2 (Sof-Dac), two patients had improved CTP scores; both scores moved from score B to score A.
Both patients were treatment naïve and received 12 weeks course of treatment. While two patients had worsened CTP scores: one went from score A to B, and one went from score B to C. These patients were also treatment naïve and received 12 weeks of therapy. No major adverse events were reported in either treatment group.
However, lethargy in one patient leading to medication nonadherence, headache in two patients, and pruritus in one patient were reported in Group 2. In contrast, no patient reported any adverse events of these types in Group 1. MELD score (mean) 11.2 ± 5.7 9.8 ± 6. The CTP score in this study did not change in the majority of the patients at the time of SVR-12, which is explained and expected because most of the patients included were classified as CTP-A in both groups at the beginning of the study. However, treatment with DAA in one study was associated with improved CTP scores and resulted in a reversal of liver decompensation state. 27 This would be important to decide on the urgency of treatment in patients with decompensated cirrhosis, or deferring the treatment after transplantation is a preferred approach.
Treatment of HCV recurrence postliver transplant with DAA has been reported with high SVR-12 of~86%-96%, and no major concerns for clinically significant drug-drug interactions with immunosuppressants, which was similar to our study with an SVR-12 reported between 86% and 100% in this subgroup population. 19,28,29 The combination of Sof-Led (Harvoni ® ) cost for 12 weeks course of therapy was around 203,868 SR per patient, while the generic sofosbuvir (Sovira ® ) combined with branded daclatasvir (Daclinza ® ) course of treatment cost was 76,524 SR, which resulted in direct cost reduction by 62%. Moreover, the cost of combining branded sofosbuvir (Sovaldi ® ) and branded daclatasvir (Daclinza ® ) for 12 weeks course of therapy was 301,140 SR, which represented a 75% potential cost inflation compared to generic sofosbuvir (Sovira ® ) and branded daclatasvir (Daclinza ® ).
This is the first prospective trial with a historical control that evaluated the effectiveness of generic sofosbuvir in combination with daclatasvir for HCV genotype 4. Our study has some limitations; first, there were differences in some baseline patients' characteristics between both groups, such as age, fibrosis score, and CTP score, which may have influenced the outcome favoring Sof-Dac. This is mainly due to a lack of randomization. Although the study was designed as noninferiority with a 9% noninferiority margin, the differences in baseline characteristics are still of concern, making it unsuitable for making the direct comparison without acknowledging the found difference. Second, patients in group 1 received ribavirin due to higher fibrosis scores. Third, our study included a small